Jules L. Derks

Clinical features of large cell neuroendocrine carcinoma : a population-based overview

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an orphan disease and few data are available on its clinical characteristics. Therefore, we analysed LCNEC registered in the Netherlands Cancer Registry, and compared data with small cell lung carcinoma (SCLC), squamous cell carcinoma (SqCC) and adenocarcinoma (AdC). Histologically confirmed LCNEC (n=952), SCLC (n=11 844), SqCC (n=19 633) and AdC (n=24 253) cases were selected from the Netherlands Cancer Registry (2003–2012). Patient characteristics, metastasis at diagnosis (2006 or later), overall survival (OS) including multivariate Cox models and first-line treatment were compared for stage I–II, III and IV disease. The number of LCNEC cases increased from 56 patients in 2003 to 143 in 2012, accounting for 0.9% of all lung cancers. Stage IV LCNEC patients (n=383) commonly had metastasis in the liver (47%), bone (32%) and brain (23%), resembling SCLC. Median OS (95% CI) of stage I–II, III and IV LCNEC patients was 32.4 (22.0–42.9), 12.6 (10.3–15.0) and 4.0 (3.5–4.6) months, respectively. Multivariate-adjusted OS of LCNEC patients resembled that of SCLC patients, and was poorer than those of SqCC and AdC patients. However, frequency of surgical resection and adjuvant chemotherapy resembled SqCC and AdC more than SCLC. Diagnosis of LCNEC has increased in recent years. The metastatic pattern of LCNEC resembles SCLC as does the OS. However, early-stage treatment strategies seem more comparable to those of SqCC and AdC. Outcome of LCNEC is poor and metastatic pattern resembles SCLC, yet stage I–II treatment corresponds more with NSCLC http://ow.ly/S37N9

Chemotherapy for pulmonary large cell neuroendocrine carcinomas : Does the regimen matter?

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC. The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003–2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as “NSCLC-t”, comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; “NSCLC-pt”, with pemetrexed treatment only; and “SCLC-t”, consisting of etoposide chemotherapy. A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n=20) and SCLC-t in 38% (n=48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0–9.9) months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0–6.9) months (hazard ratio 2.51, 95% CI 1.39–4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0–8.5) months (hazard ratio 1.66, 95% CI 1.08–2.56; p=0.020). In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC-pt and SCLC-t chemotherapy. Treatment for pulmonary LCNEC is debated; we show favourable results for standard gemcitabine NSCLC chemotherapy http://ow.ly/2Xt730a0PK0

Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome

Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly comutated with TP53) and the RB1 wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non–small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n = 37) and 72% (n = 78) of the cases, respectively. Patients with RB1 wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS [9.6; 95% confidence interval (CI), 7.7–11.6 months] than those treated with SCLC-PE [5.8 (5.5–6.1); P = 0.026]. Similar results were obtained for patients expressing RB1 in their tumors (P = 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression. Clin Cancer Res; 24(1); 33–42. ©2017 AACR.

A Population-Based Analysis of Application of WHO Nomenclature in Pathology Reports of Pulmonary Neuroendocrine Tumors

Introduction: Pulmonary neuroendocrine tumors (pNETs) are difficult to classify. We performed a population‐based analysis to investigate the application of pNET nomenclature in daily pathology practice. Methods: Conclusions from pathology reports (2003–2012) describing carcinoids, (large cell) neuroendocrine carcinomas (NECs), and carcinomas with neuroendocrine features/differentiation were retrieved from the Dutch Pathology Registry by queries on location and diagnosis and screened for terminology. Cases with a nonpulmonary or unknown origin and small cell lung cancer were excluded. Diagnoses were clustered into subgroups and the retrieved terminology was compared with the 2015 World Health Organization (WHO) diagnoses. By means of an online questionnaire, interpretation of the non‐WHO nomenclature retrieved from pathology reports was evaluated (by 35 physicians and 19 pathologists). Results: A total of 3216 unique pathology report conclusions with 55 different pNET diagnoses (n = 3052) and 20 uncertain diagnoses (n = 164) were analyzed. Non‐WHO nomenclature was used in 15% of diagnoses (n = 488). Diagnoses could be clustered into carcinoids (n = 1086), NEC (n = 1316), carcinomas with neuroendocrine features/differentiation (n = 624), and unspecified pNETs (n = 26). Non‐WHO nomenclature within these clusters was found for 7% of carcinoids, 20% of NECs, 13% of carcinomas with neuroendocrine features/differentiation, and 100% of unspecified pNETs and was observed more often in conclusions regarding biopsy or cytological specimens (62% and 12%) compared with resection specimens (26%). Analysis of the questionnaire results revealed that 4 of 19 diagnoses based on non‐WHO nomenclature were uniformly interpreted (>50% agreement) by physicians, as were 10 of 19 diagnoses by pathologists. Conclusions: In 15% of pNETs other than small cell lung cancer, a non‐WHO nomenclature diagnosis was provided, more frequently on the basis of smaller specimens. The interpretation was different between physicians and pathologists. Application of uniform nomenclature among all clinicians is advocated.

An Unmet Need in the WHO 2015 Biopsy Classification: Poorly Differentiated NSCCs with Positive Neuroendocrine Markers

To the Editor: It is with great interest that we read the recent World Health Organization (WHO) Classification 2015 of lung tumors and the state-of-the-art concise review by Travis et al. published in the Journal of Thoracic Oncology. The diagnostic criteria for small biopsy specimens are especially interesting and clinically relevant. The new classification for biopsy specimens to diagnose non–small cell lung carcinoma (NSCLC) without clear morphologic features is driven largely by immunohistochemical (IHC) markers. This classification (Fig. 1) categorizes NSCLC as follows: (1) non–small cell carcinoma (NSCC), favor adenocarcinoma (positive for thyroid transcription factor 1), (2) NSCC, favor squamous cell carcinoma (p63/p40þ), or (3) NSCC, not otherwise specified (no morphologic features and negative for IHC markers). Moreover, when neuroendocrine (NE) morphologic features are present, testing for NE markers should be performed, and when the results are positive, the diagnosis “NSCC, favor large cell NE carcinoma (LCNEC)” is preferred. Finally, the diagnostic term for NSCC with morphologic features of NE in the absence of NE IHC markers is NSCC when LCNEC is suspected but stains fail to demonstrate NE differentiation. Following this classification, one category is missing, namely, NSCC without distinct (NE) morphologic features but with positive NE IHC markers, which in this letter is referred as NSCC NE IHCþ (see Fig. 1). The value of the diagnosis NSCC NE IHCþ has been heavily debated. As many as 10% to 30% of surgically resected NSCLCs have NE differentiation in IHC staining, but no clear association with prognosis has

Neuroendocrine Cancer of the Lung: A Diagnostic Puzzle

Here we report the case of a pulmonary neuroendocrine tumor (pNET) in which the pathological diagnosis was revised several times over the course of the patients disease because of atypical behavior of the tumor; consequently, the patient was treated with various treatment schedules.

Genetics and Epigenetics of Pancreatic Neuroendocrine Tumors and Pulmonary Carcinoids

In this chapter, we give an overview of the genetic and epigenetic background of neuroendocrine tumors (NETs), in particular pancreatic and pulmonary NETs. Studying the mechanism of disease of the inherited syndromes that feature NETs has provided valuable insights that have revolutionized the therapeutic options for these tumor types: both inhibition of mTOR (mammalian target of rapamycin) signaling and inhibition of angiogenesis have become standard treatments. Although sporadic NETs harbor relatively few somatic gene mutations, these somatic mutations often affect genes that encode epigenetic regulators. Restoring the aberrant epigenetic characteristics may be an attractive approach for future treatment.

New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

&NA; Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin‐remodeling genes (e.g., menin 1 gene [MEN1]), and few affect genes of the phosphoinositide 3‐kinase (PI3K)‐AKT‐mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA‐repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto‐oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient‐tailored therapy in LCNEC.

Why we should improve current practice of diagnosing and treating pulmonary large cell neuroendocrine carcinomas in patients with advanced disease

In response to our manuscript on first-line chemotherapy treatment for metastatic pulmonary large cell neuroendocrine carcinoma (LCNEC) [1], Rossi and co-workers raised their concerns about the validity of our results by questioning the accuracy of LCNEC diagnosis on a biopsy specimen. We would like to thank the authors for their critical appraisal, underscoring the need to increase awareness among pulmonologists, oncologists and pathologists of the diagnostic issues and consequences of metastatic LCNEC diagnosed on a biopsy specimen. Current criteria for LCNEC diagnosed on a biopsy specimen are in need of improvement http://ow.ly/lRP730fu552

Abstract 340: Predictive value of KRAS mutations in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with chemotherapy (CT)

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: KRAS mutation is thought to be related with poor outcome of NSCLC pts. The predictive value of KRAS mutation for response to chemotherapy (CT) has not been established Patients and methods: From a retrospective database from 2 university hospitals all pts with advanced NSCLC treated with palliative platinum containing chemotherapy were selected. Pts were included when archive tumor tissue was available for DNA extraction. High resolution melting followed by PCR sequencing was performed for KRAS exon1 and 2. Results: KRAS mutation analysis was evaluable for 122 pts. All pts had advanced NSCLC and were no candidate for treatment with curative intent. Mean age 61 years (range 24-80 years), 81 males and 41 females. All pts received platinum-containing CT. Response was evaluable for 110 pts: 1 complete response, 21 partial response, 54 stable disease and 54 progressive disease. Median progression free survival (PFS) was 5.7 months (m) (95% CI 4.2-7.2 m), median overall survival (OS) was 7.5 m (94% CI 5.2-9.9 m). 44 pts (36%) had a KRAS mutation. 38% of pts with a KRAS mutation had as best response PD on CT, and 27% of pts without a KRAS mutation had PD, this difference was not significant. No difference in PFS and OS was observed for pts with a KRAS mutation (median PFS 5.3 m, 95% CI 3.2-7.3 m and median OS 6.2 m, 95% CI 4.8-7.3 m) and without a KRAS mutation (median PFS 6.1, 95% CI 5.0-7.2m and median OS 8.9 m, 95% CI 6.4-11.4). Conclusion: In our series KRAS mutation was not predictive for response to platinum containing CT in pts with advanced NSCLC. Furthermore, KRAS mutation was not prognostic. Additional data on specific KRAS mutations will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 340. doi:10.1158/1538-7445.AM2011-340